Identification for Predictors of Future Diabetes - Impacts of Stress and Depression ABSTRACT This grant will support Dr. Li Li a four-year period of rigorous training and experience for the development of a career as an independent investigator with expertise in glucose metabolism and experimental therapeutics. Dr. Li has a solid training, knowledge and experience in bench studies. However, she set out to develop strong interest in translational and clinical research, particularly interdisciplinary research coupling her prior laboratory experience with new interest in the effects of psychosocial stress and depression on glucose metabolism, insulin secretion/sensitivity in the past 2 years. Dr. Li completed her residency training in June of 2013 in the Department of Psychiatry at the University of Alabama at Birmingham (UAB), and seeks to expand her scientific skills and interests in the roles of psychological stress in developing Type 2 diabetes. The candidate will be under the mentorship of Dr. W Timothy Garvey, Chair of Department of Nutrition Sciences at UAB, who has extensive experience designing and implementing studies in glucose metabolism, ?-cell function, insulin resistance and diabetes. Dr. Li will also work closely with D. Richard C. Shelton, vice chair for research in the Department of Psychiatry at UAB, who is an internationally recognized patient-oriented scientist with a keen interest in experimental therapeutics. A curriculum encompassing both research and didactic training has been devised to further the training of Dr. Li, and an advisory committee of leading medical researchers will provide scientific and career advice. Both acute psychosocial stress and chronic stress states such as early life stress (ELS), may influence the pathophysiological processes of glucose metabolism and insulin sensitivity, leading to pre-diabetes and subsequent diabetes. Preliminary data indicate that both an acute psychosocial stressor and a history of ELS result in altered glucose metabolism and reduced insulin sensitivity, suggestive of an increased risk for diabetes. Major depressive disorder (MDD) usually develops as a consequence of stress. Epidemiological and clinical studies indicate that MDD is associated with increased risk of diabetes in adulthood. However, whether psychosocial stress alone or combined with MDD predisposes individuals to abnormal glucose tolerance, ?-cell dysfunction and impaired insulin sensitivity is not clear. Moreover, the underlying mechanisms for these associations are not well defined. There is a critical need to characterize the nature of the relationship between stress, depression and diabetes risk given the worldwide prevalence, and the high mortality and morbidity of Type 2 diabetes. The proposed studies will investigate the relationship between these factors in a patient-oriented project with a sample of 200 subjects. If successful, this project will give the Principal Investigator, Dr. Li Li, an opportunity to develop expertise in an interdisciplinary research area. By completing the proposed development program, the candidate will attain a comprehensive knowledge base in patient-oriented research, particularly in the area of interconnections between psychosocial stress, psychiatric disorders and metabolic disorders. It will also advance our understanding of metabolic abnormalities that characterize ELS-exposed individuals and provide insight into development of interventional strategies to slow/prevent progression of ?-cell dysfunction and insulin resistance to Type 2 diabetes. Results of this project will serve as the basis for an R01 application in a longitudinal design with the goal to determine the causal mechanisms in subjects exposed to psychosocial stress that predicts conversion to diabetes. Identifying individuals at risk for diabetes before the clinical picture emergences will afford us the opportunity to test preventive efficacy of pharmacological and non- pharmacological interventions that may have limited benefits in diabetic patients who have already developed overt diabetes and its resulting complications.